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Toxins 2016, 8(4), 110;

The Kunitz-Type Protein ShPI-1 Inhibits Serine Proteases and Voltage-Gated Potassium Channels

Centro de Estudio de Proteínas, Facultad de Biología, Universidad de la Habana, Calle 25 No. 455, 10400 La Habana, Cuba
Laboratory of Toxicology and Pharmacology, KU Leuven, Campus Gasthuisberg O&N2, Herestraat 49, P.O. Box 922, B-3000 Leuven, Belgium
Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), C/Melchor Fernández Almagro 3, Madrid E-28029, Spain
These authors contributed equally to this work.
Authors to whom correspondence should be addressed.
Academic Editors: Rong Chen and Yingliang Wu
Received: 10 March 2016 / Revised: 4 April 2016 / Accepted: 5 April 2016 / Published: 13 April 2016
(This article belongs to the Special Issue Animal Toxins and Biological Ion Channels)
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The bovine pancreatic trypsin inhibitor (BPTI)-Kunitz-type protein ShPI-1 (UniProt: P31713) is the major protease inhibitor from the sea anemone Stichodactyla helianthus. This molecule is used in biotechnology and has biomedical potential related to its anti-parasitic effect. A pseudo wild-type variant, rShPI-1A, with additional residues at the N- and C-terminal, has a similar three-dimensional structure and comparable trypsin inhibition strength. Further insights into the structure-function relationship of rShPI-1A are required in order to obtain a better understanding of the mechanism of action of this sea anemone peptide. Using enzyme kinetics, we now investigated its activity against other serine proteases. Considering previous reports of bifunctional Kunitz-type proteins from anemones, we also studied the effect of rShPI-1A on voltage-gated potassium (Kv) channels. rShPI-1A binds Kv1.1, Kv1.2, and Kv1.6 channels with IC50 values in the nM range. Hence, ShPI-1 is the first member of the sea anemone type 2 potassium channel toxins family with tight-binding potency against several proteases and different Kv1 channels. In depth sequence analysis and structural comparison of ShPI-1 with similar protease inhibitors and Kv channel toxins showed apparent non-sequence conservation for known key residues. However, we detected two subtle patterns of coordinated amino acid substitutions flanking the conserved cysteine residues at the N- and C-terminal ends. View Full-Text
Keywords: protease inhibitor; Kv channel inhibitor; sea anemone; toxin; Kunitz-type protein protease inhibitor; Kv channel inhibitor; sea anemone; toxin; Kunitz-type protein

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García-Fernández, R.; Peigneur, S.; Pons, T.; Alvarez, C.; González, L.; Chávez, M.A.; Tytgat, J. The Kunitz-Type Protein ShPI-1 Inhibits Serine Proteases and Voltage-Gated Potassium Channels. Toxins 2016, 8, 110.

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